Anti-arteriosclerotic pyridyl or imidazolyl derivatives of carbonyloxyalkyl hantzsch esters

ABSTRACT

PCT No. PCT/JP85/00449 Sec. 371 Date Apr. 7, 1986 Sec. 102(e) Date Apr. 7, 1986 PCT Filed Aug. 12, 1985 PCT Pub. No. WO86/01206 PCT Pub. Date Feb. 27, 1986.This invention relates to a 1,4-dihydropyridine-3,5-dicarboxylate derivative represented by the following general formula (I):   &lt;IMAGE&gt; (I)  wherein R means an imidazolyl or pyridyl group, R1 denotes a hydrogen or halogen atom or a nitro or trifluoromethyl group, R2 is a lower alkyl group, X is CH or N, A means a lower alkylene group,  &lt;IMAGE&gt;  B being a lower alkylene or O-lower alkylene group,  &lt;IMAGE&gt;  R4 being a hydrogen atom or lower alkyl group, or  &lt;IMAGE&gt;  m denotes a number of 1-3, and n stands for 1 or 2. The derivative has vasodilative effects, hyperkinemic effects, platelet aggregation inhibitory effects, thromboxane A2 formation inhibitory effects and so on, and are hence useful as a pharmaceutical product such as vasodilator, antihypertensive, antithrombotic agent, antiarteriosclerotic agent or the like.

TECHNICAL FIELD

This invention relates to novel 1,4-dihydropyridine-3,5-dicarboxylatederivatives, and more specifically to1,4-dihydropyridine-3,5-dicarboxylate derivatives each of which isrepresented by the following general formula (I): ##STR5## wherein Rmeans is imidazolyl or pyridyl group, R₁ denotes a hydrogen or halogenatom or a nitro or trifluoromethyl group, R₂ is a lower alkyl group, Xis CH or N, A means a lower alkylene group, ##STR6## B being a loweralkylene or O-lower alkylene group, ##STR7## R₄ being a hydrogen atom orlower alkyl group, or ##STR8## m denotes a number of 1-3, and n standsfor 1 or 2.

BACKGROUND ART

It has already been known that certain derivatives of1,4-dihydropyridine-3,5-dicarboxylic acid have pharmacological effectssuch as vasodilative effects. A variety derivatives of1,4-dihydropyridine-3,5-dicarboxylic acid have heretofore beensynthesized, pharmacological effects of which have also been studied.For example, nifedipine [Vater, W. et al, Arzneim. Forsch., 22, 1(1972)]and nicardipine [Takenaka, T. et al, Arzneim. Forsch., 26, 2172(1976)]have already been put as pharmaceutical products on the market.

These conventional derivatives of 1,4-dihydropyridine-3,5-dicarboxylicacid are however not fully satisfactory. There is thus an outstandingdemand for the development of derivatives having still betterpharmacological effects.

SUMMARY OF THE INVENTION

The present inventors have carried out an extensive research under theabove-described circumstances. As a result, it has been found that thenovel 1,4-dihydropyridine-3,5-dicarboxylate derivatives represented bythe general formula (I) have excellent pharmacological effects.

Namely, the compounds (I) of this invention have vasodilative effects,hyperkinemic effects, platelet aggregation inhibitory effects,thromboxane A₂ formation inhibitory effects and so on, and are henceuseful as pharmaceutical products such as vasodilators,antihypertensives, antithrombotic agents, anti-arteriosclerotic agents,etc. The compounds (I) of this invention are advantageous particularlyas therapeutic agents for arteriosclerosis as they have both coronaryhyperkinemic effects and thromboxane A₂ formation inhibitory effects. Inaddition, compared with the above-mentioned nifedipine and nicardipine,the compounds (I) of this invention have such advantageous features thatthey show hyperkinemic effects for the coronary artery and vertebralartery over longer periods of time and weaker heart-beat increasingeffects.

The compounds (I) of this invention can be prepared, for example, inaccordance with any one of the following Processes A-D:

Process A

Using the Hantzsch Pyridine Synthesis [Annalen der Chemie, 215, 1,72(1882)] or its modified process, the compounds (I) of this inventioncan be prepared in accordance with the following reaction scheme, inwhich all symbols have the same meaning as defined above. ##STR9##

Of the above-illustrated Processes A-1-A-7, A-1 is the Hantzsch PyridineSynthesis while Processes A-2-A-7 are its modifications.

The reactions of Process A-1-A-7 may be effected by heating theirrespective reactants in a solvent or without using any solvent, at30°-180° C. or preferably 50°-130° C. and for 2-24 hours. As thesolvent, it is possible to use a lower alcohol such as ethanol,propanol, isopropanol or n-butanol, a halogenated hydrocarbon such aschloroform, dichloroethane or trichloroethane, benzene, pyridine or thelike.

Process B ##STR10##

By the reaction between the compound (IX) and the compound (X), thecompound (I) of this invention can be prepared. This reaction may becarried out by reacting the compound (IX) with N,N'-carbonyldiimidazoleand then with the compound (X), for example, in an inert solvent. Uponconducting this reaction, it is possible to use1,8-diazabicyclo-[5.4.0]-7-undecene (hereinafter called "DBU"), sodiumalcoholate, alkali metal imidazole or the like as a reactionaccelerator. As the inert solvent, may be used tetrahydrofuran, dioxane,chloroform, methylene chloride, N,N-dimethylformamide, dimethylsulfoxide, or the like. The reaction is allowed to proceed by stirringthe reactants for 1-24 hours at room temperature or an elevatedtemperature, thereby to provide the compound (I).

Alternatively, the compound (I) may also be obtained by converting thecompound (IX) into its corresponding acid halide in a manner known perse in the art and then reacting the acid halide further with thecompound (X).

The compound (IX), one of the starting compounds, has already been known[Chem. Pharm. Bull., 27, 1426(1979)], and may be prepared by variousprocesses.

Process C ##STR11##

By reacting the compound (XI) with the compound (XII), the compound (I)of this invention can be prepared. This reaction may be effected, forexample, in an inert solvent and in the presence of a dehydrating agentsuch as dicyclohexylcarbodiimide (DCC) or the like. Upon conducting thereaction, it is feasible to use 4-dimethylaminopyridine,4-pyrrolidinopyridine or the like as a reaction accelerator.Alternatively, it is also possible to react the compound (XI) with theimidazolide which has been obtained by reacting N,N'-carbonyldiimidazolewith the compound (XII). In this case, the compound (I) iscorrespondingly obtained.

Incidentally, one of the starting compounds, the compound (XI), may beprepared in a manner similar to either one of the above-describedProcesses A-1, A-7. It may also be prepared by reacting the compound(IX) with a compound represented by the formula, HO--(CH₂)_(m) OH, in amanner similar to the above-described Process C.

Process D ##STR12##

By causing the compound (XIII) to react with the imidazole or pyridinerepresented by the formula RH, the compound (I) of this invention isobtained. It is preferred to use imidazole as its alkali metal salt. Onthe other hand, it is preferred to use pyridine as pyridyl lithium,which is obtained for example by reacting n-butyl lithium withbromopyridine at -35° C., a pyridylalkyl lithium obtained in the samemanner, or the like. The reaction may advantageously proceed by carryingit out in an inert solvent, for example, ether or tetrahydrofuran, at atemperature of -80°--30° C., for several minutes to 1 hour.

By the way, the starting compounds (XIII) for Process D may be prepared(1) in a manner similar to either one of the above-described ProcessesA-1-A-7, (2) by reacting the compound (IX) with a compound representedby the formula, ##STR13## in a manner similar to Process B, or (3) byreacting the compound (XI) with a compound represented by the formula,HOCO--A--Hal, in a manner similar to Process C.

In the above-described Processes B-D, the compound (I) of this inventionmay also be obtained by using an N-protected compound of the compounds(IX), (XI) or (XIII) and, after effecting the corresponding reaction, byremoving the protecting group. Here, as the protecting group, may beexample be used a methoxymethyl group, ethoxymethyl group or the like.These protecting groups can be easily removed by hydrolysis or the likeafter completion of the reaction.

The thus-obtained compounds (I) of this invention may be converted, inaccordance with methods known per se in the art, into their inorganic ororganic acid salts such as hydrochlorides, hydrobromides, phosphates,sulfates, oxalates, acetates, citrates, maleates, tartrates, etc.

The followings are pharmacological effects of some representativecompounds of this invention.

Using a ddY male mouse having a body weight of 35-40 g, one of therepresentative compounds of this invention was administered orally. Onehour later, citrated blood was collected. PRP (platelet-rich plasma) wasseparated. Aggregation of platelets by the addition of 12.5 μg/ml ofcollagen was observed by an aggregometer. The amount of thromboxane B₂(a stable metabolite of thromboxane A₂) formed 5 minutes later in theliquid reaction mixture was measured by the RIA method. Results areshown in Table 1, in terms of percent inhibition against the formationof thromboxane B₂ (TXB₂).

                  TABLE 1                                                         ______________________________________                                                    Dose     Percent inhibition against                               Compound    (mg/kg)  TXB.sub.2 formation (%)                                  ______________________________________                                        Compound     30      42                                                       of Ex. 2    100      72                                                       Compound     30      74                                                       of Ex. 6    100      95                                                       Compound     30      60                                                       of Ex. 8    100      72                                                       Compound     30      52                                                       of Ex. 14   100      83                                                       Compound     30      75                                                       of Ex. 16   100      94                                                       ______________________________________                                    

As shown in Table 1, the compounds of this invention have extremelystrong thromboxane A₂ formation inhibitory effects.

The compounds of this invention have hyperkinemic effects for thecoronary and vertebral arteries. Their advantageous feature is that theycan show such effects over prolonged periods of time. Although theyincrease the amount of blood which flows through the coronary artery,they have another advantageous feature that they show weak heart-beatincreasing effects.

These effects of the compounds of this invention indicate that they areuseful not only as vasodilators but also as therapeutic drugs forarteriosclerosis.

When formulating the compounds of this invention into pharmaceuticalcompositions, liquid or solid carriers or diluents may be used. As thesecarriers, may be mentioned various excipients, binders, lubricants,emulsifiers, etc., which are by themselves known in the field ofproduction of pharmaceutical compositions. Illustrative of carriers ordiluents may include starches such as potato starch, wheat starch, cornstarch and rice starch; saccharides such as lactose, sucrose, glucose,mannitol and sorbitol; celluloses such as crystalline cellulose, calciumcarboxycellulose and moderately-substituted hydroxypropylcellulose;inorganic materials such as potassium phosphate, calcium sulfate,calcium carbonate and talc; binders such as gelatin, gum arabic,methylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidoneand hydroxypropylcellulose; anionic surfactants of the polyhydricalcohol ester type, such as fatty acid monoglycerides, sorbitan fattyacid esters, sucrose and polyglycerol fatty acid esters; anionicsurfactants of the polyoxyethylene type; and so on.

These pharmaceutical compositions may be processed into anypharmaceutically-known dosable forms such as suppositories, powder,granules, tablets, troches, liquid preparations, injectablepreparations, suspensions, etc.

Pharmaceutical compositions of the compounds of this invention may beadministered in any route, namely, orally, or parenterally, e.g.,intravenously, sublingally or via the rectum. Oral administration ishowever preferred when administered for long periods of time.

Dose may be subject to variations as needed. For example, the compounds(I) of this invention may each be administered at a dose of about 1-500mg/body/day with 50-200 mg/body/day being preferred. The acute toxicitylevels (LD₅₀) of the compounds of this invention are about 300 mg/kg(rat) when administered orally and 30-50 mg/kg (rat) when administeredintravenously. Their toxicity levels are hence extremely low.

[EXAMPLES]

This invention will next be described by the following Examples.

EXAMPLE 1 3-Methyl5-[2-[6-(1-imidazolyl)-hexanoyloxy]-ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

(1) To an anhydrous N,N-dimethylformamide solution containing 170 mg of6-bromohexanoic acid, 200 mg of N,N'-carbonyldiimidazole was added, andthe resultant mixture was stirred at room temperature for 75 minutes.

To the reaction mixture, were then added an anhydrousN,N-dimethylformamide solution containing 323 mg of 3-methyl5-(hydroxyethyl)1-methoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylateand a solution which had been prepared by adding 116 mg of imidazole toan anhydrous N,N-dimethylformamide suspension containing 74 mg of 50%sodium hydride. The resultant mixture was stirred at room temperaturefor 19 hours.

After completion of the reaction, 50 ml of a saturated aqueous solutionof ammonium chloride was added and the resultant mixture was extractedwith ethyl acetate. The extract was successively washed first with asaturated aqueous solution of sodium hydrogencarbonate and then with asaturated brine, followed by its drying.

Upon purification of the residue, which had been obtained by distillingoff the solvent, by silica gel column chromatography, 261 mg of 3-methyl5-[2-[6-(1-imidazolyl)-hexanoyloxy]-ethyl]1-methoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylatewas obtained as a light yellowish oily substance (yield: 58.1%).

    ______________________________________                                        IR ν .sub.max.sup.filmcm.sup.-1 :                                          2936, 1735, 1695, 1640, 1526, 1348, 1212, 1155,                               1070, 750                                                                     NMR δ (CDCl.sub.3):                                                     1.14-1.92   (6H, m, (C .sub.--H.sub.2).sub.3)                                 2.24        (2H, t, J=7Hz, C .sub.--H.sub.2 COO)                              2.50        (6H, s, C .sub.--H.sub.3 × 2)                               3.28        (3H, s, OC .sub.--H.sub.3)                                        3.66        (3H, s, COOC .sub.--H.sub.3)                                      3.90                                                                                       ##STR14##                                                        4.26        (4H, s, COOC .sub.--H.sub.2 C .sub.--H.sub.2.OCO)                 4.76                                                                                       ##STR15##                                                        -5.12       (1H, s, C.sub.4 .sub.--H)                                         6.84, 6.92                                                                                 ##STR16##                                                        7.82-8.04                                                                                  ##STR17##                                                        ______________________________________                                    

(2) Dissolved in tetrahydrofuran was 344 mg of the above-obtained1-methoxymethyl derivative, followed by an addition of 1.28 ml of6N-hydrochloric acid. The resultant mixture was stirred at roomtemperature for 3.5 hours. After the reaction, the solvent was distilledoff, a saturated aqueous solution of sodium hydrogencarbonate was addedto the residue to make the residue alkaline, and the alkaline residuewas then extracted with chloroform. The chloroform layer was separated,washed with water and then dried. The solvent was thereafter distilledoff. The thus-obtained residue was purified by silica gel columnchromatography, thereby obtaining 211 mg of 3-methyl5-[2-[6-(1-imidazolyl)-hexanoyloxy]-ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylateas a light-yellowish viscous oily substance (yield: 66.3%).

    ______________________________________                                        IR ν .sub.max.sup.liq.filmcm.sup.-1 ;                                      3509, 3321, 3173, 2935, 1734, 1691, 1642, 1523,                               1502, 1346, 1208, 1112, 745                                                   NMR δ (CDCl.sub.3):                                                     1.10-1.90 (6H, m, (C .sub.--H.sub.2).sub.3)                                   2.27      (2H, t, J=6.6Hz, C .sub.--H.sub.2 COO)                              2.34, 2.38                                                                              (3H × 2, s × 2, C .sub.--H.sub.3 × 2)             3.66      (3H, s, COOC .sub.--H.sub.3)                                        3.98                                                                                     ##STR18##                                                          4.28      (4H, s, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OCO)                   5.12      (1H, s, C.sub.4 .sub.--H)                                           6.96, 7.08                                                                               ##STR19##                                                          7.52                                                                                     ##STR20##                                                          7.68                                                                                     ##STR21##                                                          8.02                                                                                     ##STR22##                                                          8.15                                                                                     ##STR23##                                                          ______________________________________                                    

EXAMPLE 2 3-Ethyl5-[2-[4-[2-(1-imidazolyl)-ethoxy]-benzoyloxy]-ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Added to an anhydrous N,N-dimethylformamide solution containing 300 mgof 4-[2-(1-imidazolyl)ethoxy]-benzoic acid was 334 mg ofN,N'-carbonyldiimidazole. The resultant mixture was stirred at roomtemperature for 100 minutes.

An anhydrous N,N-dimethylformamide solution containing 656 mg of 3-ethyl5-(2-hydroxyethyl)2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and236 mg of 1,8-diazabicyclo-[5.4.0]-7-undecene (DBU) was then added, andthe resultant mixture was stirred for 13 hours.

After the reaction, 100 ml of a saturated aqueous solution of ammoniumchloride was added and the resultant mixture was extracted with ethylacetate. The ethyl acetate layer was separated, washed with a saturatedbrine, and then dried. The solvent was distilled off and the residue waspurified by silica gel column chromatography to obtain 75 mg of 3-ethyl5-[2-[4-[2-(1-imidazolyl)-ethoxy]-benzoyloxy]-ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylateas colorless amorphous powder (yield: 96.2%).

    ______________________________________                                        IR ν .sub.max.sup.KBr cm.sup.-1 :                                          3351, 2917, 1691, 1645, 1604, 1522, 1347, 1250,                               1208, 1003, 766                                                               NMR δ(CDCl.sub.3):                                                      2.16        (3H, t, J=6Hz, CH.sub.2 C .sub.--H.sub.3)                         2.32, 2.36  (3H × 2, s × 2, C .sub.--H.sub.3 × 2)           4.06        (2H, q, J=6Hz, COOC .sub.--H.sub.2 CH.sub.3)                      4.20-4.60   (8H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC,                              ##STR24##                                                        5.10        (1H, s, C.sub.4 .sub.--H)                                         6.86                                                                                       ##STR25##                                                        7.10                                                                                       ##STR26##                                                        7.66                                                                                       ##STR27##                                                        7.88                                                                                       ##STR28##                                                        8.10                                                                                       ##STR29##                                                        ______________________________________                                    

EXAMPLE 3 3-Methyl5-[2-[4-(1-imidazolylmethyl)benzoyloxy]-ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

(1) Added to an anhydrous N,N-dimethylformamide solution containing 340mg of3-methoxycarbonyl-1-methoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylicacid was 220 mg of N,N'-carbonyldiimidazole. The resultant mixture wasstirred at room temperature for 70 minutes. Then, an anydrousN,N-dimethylformamide solution containing 450 mg of hydroxyethyl4-(1-imidazolylmethyl)-benzoate and 150 mg of DBU was added and theresultant mixture was stirred for 16 hours. After the reaction, 80 ml ofa saturated aqueous solution of ammonium chloride was added and theresultant mixture was extracted with ethyl acetate. The ethyl acetatelayer was separated, washed with a saturated brine, and then dried. Thesolvent was distilled off and the residue was purified by silica gelcolumn chromatography to obtain 437 mg of 3-methyl5-[2-[4-(1-imidazolylmethyl)-benzoyloxy]-ethyl]1-methoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylateas a light-yellowish viscous oily substance (yield: 80.0%).

    ______________________________________                                        IR ν .sub.max.sup.liq.filmcm.sup.-1 :                                      3556, 3349, 3102, 2938, 1717, 1699, 1637, 1582,                               1347, 1272, 1209, 1156, 1064, 740                                             NMR δ(CDCl.sub.3):                                                      2.50, 2.54  (3H × 2, s × 2, C .sub.--H.sub.3 × 2)           3.32        (3H, s, OC .sub.--H.sub.3)                                        3.66        (3H, s, COOC .sub.--H.sub.3)                                      4.30-4.70   (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                 4.82                                                                                       ##STR30##                                                        5.18        (1H, s, C.sub.4 .sub.--H)                                         5.20                                                                                       ##STR31##                                                        6.96                                                                                       ##STR32##                                                        7.61                                                                                       ##STR33##                                                        ______________________________________                                    

(2) Using 254 mg of the thus-obtained 1-methoxymethyl derivative,hydrolysis treatment and removal of the protecting group were effectedin the same manner as in Example 1-2) to obtain 208 mg of 3-methyl5-[2-[4-(1-imidazolylmethyl)-benzoyloxy]-ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylateas yellowish amorphous powder (yield: 91.6%).

    ______________________________________                                        IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3319, 2918, 1722, 1688, 1523, 1348, 1270, 1209,                               1090, 1015, 747                                                               NMR δ(CDCl.sub.3):                                                      2.34, 2.38  (3H × 2, s × 2, C .sub.--H.sub.3 × 2)           3.62        (3H, s, COOC .sub.--H.sub.3)                                      4.20-4.60   (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                 5.10        (1H, s, C.sub.4 .sub.--H)                                         5.21                                                                                       ##STR34##                                                        6.24                                                                                       ##STR35##                                                        6.96                                                                                       ##STR36##                                                        8.06                                                                                       ##STR37##                                                        ______________________________________                                    

EXAMPLE 4 3-Methyl5-[2-[3-[4-(1-imidazolylmethyl)phenyl]-acryloyloxy]-ethyl]2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate

To an anhydrous N,N-dimethylformamide solution containing 200 mg of4-(1-imidazolylmethyl)cinnamic acid, 213 mg of N,N'-carbonyldiimidazolewas added. The resultant mixture was stirred at room temperature for 80minutes.

An anhydrous N,N-dimethylformamide solution which contained 349 mg of3-methyl5-(2-hydroxyethyl)2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand 147 mg of DBU was thereafter added. The resultant mixture wasstirred for 13 hours. After adding 70 ml of a saturated aqueous solutionof ammonium chloride to the reaction mixture, the reaction mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed with asaturated brine and then dried. The solvent was distilled off and theresidue was purified by silica gel column chromatography. From a 50:2mixed solvent of chloroform and methanol, 272 mg of 3-methyl5-[2-[3-[4-(1-imidazolylmethyl)phenyl]-acryloyloxy]-ethyl]2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylatewas obtained as yellowish amorphous powder (yield: 57.2%).

    ______________________________________                                        IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3332, 2940, 1689, 1635, 1498, 1306, 1209, 1114,                               750                                                                           NMR δ(CDCl.sub.3):                                                      2.24, 2.28                                                                              (3H × 2, s × 2, C .sub.--H.sub.3 × 2)             3.60      (3H, s, COOC .sub.--H.sub.3)                                        4.20-4.50 (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                   5.20                                                                                     ##STR38##                                                          5.24      (1H, s, C.sub.4 .sub.--H)                                           6.46                                                                                     ##STR39##                                                          6.98                                                                                     ##STR40##                                                          8.52                                                                                     ##STR41##                                                          8.98                                                                                     ##STR42##                                                          ______________________________________                                    

EXAMPLE 5 3-Methyl5-[2-[3-(1-imidazolyl)-3-[4-(1-imidazolylmethyl)phenyl]-propionyloxy]ethyl]2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate

By using a 10:1 mixed solvent of chloroform and methanol upon conductingthe purification by column chromatography in Example 4, 49 mg of thetitle compound was obtained as a yellowish viscous oily substance(yield: 9.2%).

    ______________________________________                                        IR ν .sub.max.sup.liq.filmcm.sup.-1 :                                      3260, 2943, 1735, 1685, 1500, 1431, 1213, 1114,                               749                                                                           NMR δ(CDCl.sub.3):                                                      2.24, 2.26 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.20                                                                                      ##STR43##                                                         3.62       (3H, s, COOC .sub.--H.sub.3)                                       4.05-4.35  (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                  5.14                                                                                      ##STR44##                                                         5.22       (1H, s, C.sub.4 .sub.--H)                                          5.76                                                                                      ##STR45##                                                         6.94, 6.98                                                                                ##STR46##                                                                     ##STR47##                                                         8.52                                                                                      ##STR48##                                                         ______________________________________                                    

EXAMPLE 6 3-Ethyl5-[3-[4-[2-(1-imidazolyl)ethoxyl]benzoyloxy]propyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

After adding 2.3 ml of thionyl chloride dropwise to 10 g of2,6-dimethyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylicacid in a mixed solvent consisting of 16 ml of anhydrousN,N-dimethylformamide and 52 ml of methylene chloride while maintainingthe internal temperature below -5° C. with salt-ice cooling, theresultant mixture was stirred for 1 hour. Thereafter, while maintainingthe internal temperature below -5° C., 7.54 g of 3-hydroxypropyl4-[2-(1-imidazolyl)ethoxy]benzoate was added. The resulting mixture wasstirred for 1 hour. Ice water was added to the reaction mixture,followed by an addition of an aqueous solution of sodium carbonate tomake the mixture alkaline. The mixture was then extracted withchloroform. After washing the chloroform layer with water, the solventswere distilled off and the residue was purified by silica gel columnchromatography to obtain 16 g of 3-ethyl5-[3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate(yield: 90%).

    ______________________________________                                        Molecular formula:                                                            C.sub.32 H.sub.34 N.sub.4 O.sub.9                                             Appearance:                                                                   Yellowish powder                                                              IR ν .sub.max.sup.KBrcm.sup.-1 :                                           3319, 2934, 1689, 1522, 1348, 1272, 1209, 1166, 1096, 767.                    NMR δ(CDCl.sub.3):                                                      1.22   (3H, t, J=7Hz, CH.sub.2 C .sub.--H.sub.3)                              2.06   (2H, quin, J=6Hz, CH.sub.2 C .sub.--H.sub.2 CH.sub.2)                  2.34   (6H, s, C .sub.--H.sub.3 × 2)                                    4.07, 4.10                                                                           (1H × 2, quin × 2, J=7Hz, C .sub.--H.sub.2 CH.sub.3)       4.15-4.40                                                                             ##STR49##                                                                     ##STR50##                                                             5.08   (1H, s, C.sub.4 .sub.--H)                                              6.40                                                                                  ##STR51##                                                             6.85                                                                                  ##STR52##                                                             7.05, 7.08                                                                            ##STR53##                                                             7.36                                                                                  ##STR54##                                                             7.61                                                                                  ##STR55##                                                             7.93                                                                                  ##STR56##                                                             8.12                                                                                  ##STR57##                                                             ______________________________________                                    

The free base was converted to its hydrochloride in an HCl-saturatedethanol. Upon recrystallization of from ethanol, 3-ethyl5-[3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylatehydrochloride was obtained as light-yellowish platy crystals (m.p.147°-149° C.).

    ______________________________________                                        Molecular formula:                                                            C.sub.32 H.sub.34 N.sub.4 O.sub.9.HCl                                         Appearance:                                                                   Light-yellowish platy crystals                                                (m.p. 147-149° C.)                                                     IR ν .sub.max.sup.KBrcm.sup.-1 :                                           3393, 3063, 1705, 1523, 1486, 1350, 1270, 1201, 1168, 768                     NMR δ(CDCl.sub.3):                                                      1.22    (3H, t, J=7Hz, CH.sub.2 C .sub.--H.sub.3)                             2.08    (2H, broad quin, J=5Hz,                                                       CH.sub.2 C .sub.--H.sub.2 CH.sub.2)                                   2.32, 2.39                                                                            (3H × 2, s × 2, C .sub.--H.sub.3 × 2)               4.05, 4.07                                                                            (1H × 2, quin × 2, J=7Hz, C .sub.--H.sub.2 CH.sub.3)      4.15-4.35                                                                              ##STR58##                                                            4.40-4.60                                                                             (2H, broad m, OC .sub.--H.sub.2 CH.sub.2)                             4.75-4.85                                                                              ##STR59##                                                            5.01    (1H, s, C.sub.4 .sub.--H)                                             6.66                                                                                   ##STR60##                                                            6.84                                                                                   ##STR61##                                                            7.33                                                                                   ##STR62##                                                            7.61                                                                                   ##STR63##                                                            7.88                                                                                   ##STR64##                                                            8.03                                                                                   ##STR65##                                                            7.38                                                                                   ##STR66##                                                            9.67                                                                                   ##STR67##                                                            ______________________________________                                    

EXAMPLES 7-22

The following compounds were prepared in the same manner as in Examples1-6.

EXAMPLE 7 3-Methyl5-[2-[11-(1-imidazolyl)undecanoyloxy]ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula:                                                            C.sub.32 H.sub.42 N.sub.4 O.sub.8                                             Appearance:                                                                   Light-yellowish viscous oily substance                                        IR ν .sub.max.sup.liq.filmcm.sup.-1 :                                      3507, 3321, 3180, 2924, 1734, 1700, 1648, 1523, 1502, 1347, 1211,             1114, 751                                                                     NMR δ(CDCl.sub.3):                                                      1.00-1.94  (16H, broad m, (C .sub.--H.sub.2).sub.8)                           2.26       (2H, t, J=6.6Hz, C .sub.--H.sub.2 COO)                             2.35, 2.37 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.65       (3H, s, COOC .sub.--H.sub.3)                                       3.96                                                                                      ##STR68##                                                         4.26       (4H, s, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                  5.12       (1H, s, C.sub.4 .sub.--H)                                          6.96, 7.08                                                                                ##STR69##                                                         7.16                                                                                      ##STR70##                                                         7.40                                                                                      ##STR71##                                                         7.52                                                                                      ##STR72##                                                         7.68                                                                                      ##STR73##                                                         8.02                                                                                      ##STR74##                                                         8.14                                                                                      ##STR75##                                                         ______________________________________                                    

EXAMPLE 8 3-Methyl5-[2-[3-[4-(1-imidazolylmethyl)-phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula:                                                            C.sub.31 H.sub.30 N.sub.4 O.sub.8                                             Appearance:                                                                   Yellowish amorphous powder                                                    IR ν .sub.max.sup.KBrcm.sup.-1 :                                           3393, 2940, 1695, 1635, 1523, 1347, 1211, 1115, 747                           NMR δ(CDCl.sub.3):                                                      2.34, 2.36 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.60       (3H, s, COOC .sub.--H.sub.3)                                       4.18-4.50  (4H, broad m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)            5.08       (1H, s, C.sub.4 .sub.--H)                                          5.14                                                                                      ##STR76##                                                         6.32                                                                                      ##STR77##                                                         6.64                                                                                      ##STR78##                                                         6.90                                                                                      ##STR79##                                                         7.88                                                                                      ##STR80##                                                         8.06                                                                                      ##STR81##                                                         ______________________________________                                    

EXAMPLE 9 3-Methyl5-[2-[3-(1-imidazolyl)-3-[4-(1-imidazolylmethyl)phenyl]propionyloxy]ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula:                                                            C.sub.34 H.sub.34 N.sub.6 O.sub.8                                             Appearance:                                                                   Yellowish amorphous powder                                                    IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3327, 2940, 1734, 1687, 1652, 1522, 1348, 1210,                               1115, 746                                                                     NMR δ(CDCl.sub.3):                                                      2.26, 2.34 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.16                                                                                      ##STR82##                                                         3.62       (3H, s, COOC .sub.--H.sub.3)                                       4.00-4.30  (4H, broad m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)            5.07       (1H, s, C.sub.4 .sub.--H)                                          5.10                                                                                      ##STR83##                                                         5.72                                                                                      ##STR84##                                                         6.90                                                                                      ##STR85##                                                         7.94                                                                                      ##STR86##                                                         8.08                                                                                      ##STR87##                                                         ______________________________________                                    

EXAMPLE 10 3-Methyl5-[2-[4-[6-(1-imidazolyl)hexyloxy]benzoyloxy]ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula:                                                            C.sub.34 H.sub.38 N.sub.4 O.sub.9                                             Appearance:                                                                   Yellowish amorphous powder                                                    IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3330, 2921, 1695, 1640, 1523, 1346, 1271, 1206,                               1090, 1015, 751                                                               NMR δ(CDCl.sub.3):                                                      1.20-1.95                                                                              (8H, m, (C .sub.--H.sub.2).sub.4)                                    2.34, 2.36                                                                             (3H × 2, s × 2, C .sub.--H.sub.3 × 2)              3.60     (3H, s, COOC .sub.--H.sub.3)                                         3.80-4.10                                                                               ##STR88##                                                           4.20-4.60                                                                              (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                    5.10     (1H, s, C.sub.4 .sub.--H)                                            6.92, 7.06                                                                              ##STR89##                                                           7.86                                                                                    ##STR90##                                                           8.10                                                                                    ##STR91##                                                           ______________________________________                                    

EXAMPLE 11 3-Methyl5-[2-[2-methyl-3-[4-(3-pyridylmethyl)phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula:                                                            C.sub.34 H.sub.33 N.sub.3 O.sub.8                                             Appearance:                                                                   Yellowish amorphous powder                                                    IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3335, 2939, 1699, 1644, 1525, 1347, 1208, 1113,                               1093, 746                                                                     NMR δ(CDCl.sub.3):                                                      2.08                                                                                      ##STR92##                                                         2.36, 2.38 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.60       (3H, s, COOC .sub.--H.sub.3)                                       4.04                                                                                      ##STR93##                                                         4.20-4.52  (4H, broad m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)            5.14       (1H, s, C.sub.4 .sub.--H)                                          6.24                                                                                      ##STR94##                                                         7.96                                                                                      ##STR95##                                                         8.12                                                                                      ##STR96##                                                         8.44-8.60                                                                                 ##STR97##                                                         ______________________________________                                    

EXAMPLE 12 3-Methyl5-[2-[2-methyl-3-[4-(3-pyridylmethyl)phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula:                                                            C.sub.34 H.sub.33 N.sub.3 O.sub.8                                             Appearance:                                                                   Yellowish amorphous powder                                                    IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3397, 1699, 1630, 1527, 1490, 1350, 1207, 1106,                               750, 710                                                                      NMR δ(CDCl.sub.3):                                                      2.03                                                                                      ##STR98##                                                         2.29, 2.36 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.53       (3H, s, COOC .sub.--H.sub.3)                                       4.01                                                                                      ##STR99##                                                         4.20-4.45  (4H, broad m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)            5.79       (1H, s, C.sub.4 .sub.--H)                                          6.59                                                                                      ##STR100##                                                        8.42-8.55                                                                                 ##STR101##                                                        ______________________________________                                    

EXAMPLE 13 3-Methyl5-[2-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]ethyl]2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.30 H.sub.30 N.sub.4 O.sub.9                          Appearance: Yellowish amorphous powder                                        IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3330, 2942, 1694, 1604, 1526, 1353, 1271, 1248, 1209, 1104, 767               NMR δ(CDCl.sub.3):                                                      2.29, 2.34    (3H × 2, s × 2, C .sub.--H.sub.3 × 2)         3.55          (3H, s, COOC .sub.--H.sub.3)                                    4.25-4.45     (8H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOCand                            ##STR102##                                                     5.77          (1H, s, C.sub.4 .sub.--H)                                       6.32                                                                                         ##STR103##                                                     6.84                                                                                         ##STR104##                                                     7.05, 7.08                                                                                   ##STR105##                                                     7.61                                                                                         ##STR106##                                                     7.87                                                                                         ##STR107##                                                     ______________________________________                                    

EXAMPLE 14 3-Methyl5-[2-[3-[4-(1-imidazolylmethyl)phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.31 H.sub.30 FN.sub.3 O.sub.6                         Appearance: Light-yellowish amorphous powder                                  IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3402, 2939, 1692, 1635, 1490, 1305, 1210, 1114, 756                           NMR δ(CDCl.sub.3):                                                      2.32, 2.34 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.56       (3H, s, COOC .sub.--H.sub.3)                                       4.10-4.50  (4H, broad m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)            5.16                                                                                      ##STR108##                                                        5.28       (1H, s, C.sub.4 .sub.--H)                                          6.38                                                                                      ##STR109##                                                        6.39                                                                                      ##STR110##                                                        6.95, 7.14                                                                                ##STR111##                                                        7.64                                                                                      ##STR112##                                                        ______________________________________                                    

EXAMPLE 15 3-Methyl5-[2-[3-[4-(1-imidazolymethyl)phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.31 H.sub.29 Cl.sub.2 N.sub.3 O.sub.6                 Appearance: Light-yellowish amorphous powder                                  IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3406, 2917, 1693, 1635, 1496, 1304, 1274, 1207, 1134, 750                     NMR δ(CDCl.sub.3):                                                      2.26, 2.32 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.56       (3H, s, COOC .sub.--H.sub.3)                                       4.20-4.50  (4H, b.m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                5.16                                                                                      ##STR113##                                                        5.48       (1H, s, C.sub.4 .sub.--H)                                          6.36                                                                                      ##STR114##                                                        6.64                                                                                      ##STR115##                                                        6.92                                                                                      ##STR116##                                                        ______________________________________                                    

EXAMPLE 16 3-Methyl5-[2-[4-[2-(1-imidazolyl)ethoxy]-benzoyloxy]ethyl]2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.30 H.sub.29 Cl.sub.2 N.sub.3 O.sub.7                 Appearance: Colorless amorphous powder                                        IR.sup.KBr .sub.maxcm.sup.-1 :                                                3405, 2938, 1693, 1644, 1623, 1505, 1418, 1303,                               1247, 1208, 1134, 1050, 770                                                   NMR δ(CDCl.sub.3):                                                      2.28       (6H, s, C .sub.--H.sub.3 × 2)                                3.56       (3H, s, COOC .sub.--H.sub.3)                                       4.20-4.50  (8H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOCand                            ##STR117##                                                        5.48       (1H, s, C.sub.4 .sub.--H)                                          6.36                                                                                      ##STR118##                                                        6.86                                                                                      ##STR119##                                                        7.62                                                                                      ##STR120##                                                        7.90                                                                                      ##STR121##                                                        ______________________________________                                    

EXAMPLE 17 3-Methyl5-[2-[3-(1-imidazolyl)-3-[4-(1-imidazdolylmethyl)phenyl]propionyloxy]ethyl]2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Appearance: Colorless amorphous powder                                        IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3261, 2942, 1734, 1688, 1640, 1499, 1376, 1209,                               1109, 750                                                                     NMR δ(CDCl.sub.3):                                                      2.30       (6H, s, C .sub.--H.sub.3 × 2)                                3.16                                                                                      ##STR122##                                                        3.58       (3H, s, COOC .sub.--H.sub.3)                                       4.00-4.34  (4H, broad m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)            5.12                                                                                      ##STR123##                                                        5.44       (1H, s, C.sub.4 .sub.--H)                                          5.64                                                                                      ##STR124##                                                        6.92                                                                                      ##STR125##                                                                    ##STR126##                                                        7.56                                                                                      ##STR127##                                                        8.08                                                                                      ##STR128##                                                        ______________________________________                                    

EXAMPLE 18 3-Ethyl5-[3-[3-[4-(1-imidazolylmethyl)phenyl]acryloyloxy]propyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.33 H.sub.34 N.sub.4 O.sub.8                          Appearance: Yellowish amorphous powder                                        IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3323, 2921, 1693, 1635, 1523, 1347, 1206, 1114, 744                           NMR δ(CDCl.sub.3):                                                      1.23       (3H, t, J=6Hz, CH.sub.2 C .sub.--H.sub.3)                          1.80-2.10  (2H, m, CH.sub.2 C .sub.--H.sub.2 CH.sub.2)                        2.33, 2.36 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.90-4.30  (6H, m, COOC .sub.--H.sub.2 CH.sub.3 and                                      COOC .sub.--H.sub.2 CH.sub.2 C .sub.--H.sub.2 OOC)                 5.10       (1H, s, C.sub.4 .sub.--H)                                          5.14                                                                                      ##STR129##                                                        6.20                                                                                      ##STR130##                                                        6.38                                                                                      ##STR131##                                                        6.90                                                                                      ##STR132##                                                        8.00                                                                                      ##STR133##                                                        8.13                                                                                      ##STR134##                                                        ______________________________________                                    

EXAMPLE 19 3-Methyl5-[2-[3-[4-(1-imidazolylmethyl)phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.31 H.sub.30 N.sub.4 O.sub.8                          Appearance: Yellowish amorphous powder                                        IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3333, 2940, 1694, 1636, 1526, 1307, 1208, 1110, 782                           NMR δ(CDCl.sub.3):                                                      2.30, 2.37 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.53       (3H, s, COOC .sub.--H.sub.3)                                       4.20-4.40  (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                  5.16                                                                                      ##STR135##                                                        5.79       (1H, s, C.sub.4 .sub.--H)                                          6.10                                                                                      ##STR136##                                                        6.33                                                                                      ##STR137##                                                        6.92, 7.11                                                                                ##STR138##                                                        ______________________________________                                    

EXAMPLE 20 3-Methyl5-[2-[3-[4-(1-imidazolylmethyl)phenyl]acryloyloxy]ethyl]2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.32 H.sub.30 F.sub.3 N.sub.3 O.sub.6                  Appearance: Light-yellowish amorphous powder                                  IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3332, 2939, 1695, 1635, 1497, 1307, 1209, 1112, 761                           NMR δ(CDCl.sub.3):                                                      2.30, 2.34 (3H × 2, s × 2, C .sub.--H.sub.3 × 2)            3.56       (3H, s, COOC .sub.--H.sub.3)                                       4.00-4.50  (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)                  5.20                                                                                      ##STR139##                                                        5.62       (1H, broad s, C.sub.4 .sub.--H)                                    6.38                                                                                      ##STR140##                                                        6.40                                                                                      ##STR141##                                                        6.98                                                                                      ##STR142##                                                                    ##STR143##                                                        ______________________________________                                    

EXAMPLE 21 3-Ethyl5-[2-[3-(1-imidazolyl)-3-[4-(1-imidazolylmethyl)phenyl]propionyloxy]ethyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.36 H.sub.38 N.sub.6 O.sub.8                          Appearance: Yellowish viscous oily substance                                  IR ν .sub.max.sup.liq.filmcm.sup.-1 :                                      3268, 2970, 1732, 1685, 1522, 1348, 1200, 1113, 750                           NMR δ(CDCl.sub.3):                                                      2.22       (3H, t, J=7Hz, CH.sub.2 C .sub.--H.sub.3)                          1.84       (2H, broad t, J=6Hz,                                                          COOCH.sub.2 C .sub.--H.sub.2 CH.sub.2 OOC)                         2.34       (6H, s, C .sub.--H.sub.3 × 2)                                3.22                                                                                      ##STR144##                                                        3.70-4.30  (6H, m, C .sub.--H.sub.2 CH.sub.3 and                                         COOC .sub.--H.sub.2 CH.sub.2 C .sub.--H.sub.2 OOC)                 5.10       (1H, s, C.sub.4 .sub.--H)                                          5.16                                                                                      ##STR145##                                                        5.78                                                                                      ##STR146##                                                        6.96, 7,00                                                                                ##STR147##                                                                    ##STR148##                                                        8.02                                                                                      ##STR149##                                                        8.10                                                                                      ##STR150##                                                        8.18                                                                                      ##STR151##                                                        ______________________________________                                    

EXAMPLE 22 3-Methyl5-[2-[3-(1-imidazolyl)-3-[4-(1-imidazolylmethyl)phenyl]propionyloxy]ethyl]2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate

    ______________________________________                                        Molecular formula: C.sub.35 H.sub.34 F.sub.3 N.sub.5 O.sub.6                  Appearance: Light-yellowish amorphous powder                                  IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3366, 1734, 1690, 1407, 1308, 1210, 1112, 764                                 NMR δ(CDCl.sub.3):                                                      2.30          (6H, s, C .sub.--H.sub.3 × 2)                             3.14                                                                                         ##STR152##                                                     3.58          (3H, s, COOC .sub.--H.sub.3)                                    3.90-4.40     (4H, m, COOC .sub.--H.sub.2 C .sub.--H.sub.2 OOC)               5.14                                                                                         ##STR153##                                                     5.58          (1H, broad s, C.sub.4 .sub.--H)                                 5.74                                                                                         ##STR154##                                                     6.94                                                                                         ##STR155##                                                                    ##STR156##                                                     ______________________________________                                    

EXAMPLE 23 3-Ethyl5-[3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl]2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

(1) After adding at room temperature 4.1 ml of diketene dropwise to 10 gof 3-hydroxypropyl 4-[2-(1-imidazolyl)ethoxy]benzoate dissolved in 300ml of chloroform, the resultant mixture was stirred for further 18hours. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography to obtain10.1 g of 3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl acetoacetate ascolorless crystals (m.p. 49.5°-51.5° C.; yield: 78%)

    ______________________________________                                                IR ν.sup.KBr .sub.maxcm.sup.-1 :                                           3410, 1700, 1275, 1250, 1170                                          NMR δ(CDCl.sub.3):                                                      2.12       (2H, quin, J=6.2Hz, CH.sub.2 C .sub.--H.sub.2 CH.sub.2)            2.27                                                                                      ##STR157##                                                        3.47                                                                                      ##STR158##                                                        4.27                                                                                      ##STR159##                                                        4.32                                                                                      ##STR160##                                                        4.37                                                                                      ##STR161##                                                        4.38                                                                                      ##STR162##                                                        6.89                                                                                      ##STR163##                                                        7.05, 7.08                                                                                ##STR164##                                                        7.60                                                                                      ##STR165##                                                        7.98                                                                                      ##STR166##                                                        ______________________________________                                    

(2) Added to 5 g of the above-obtained acetoacetate dissolved in 50 mlof benzene were 2.1 g of 3-nitrobenzaldehyde and 0.5 ml of piperidine.After fitting a Dean-Stark water separator, the mixture was refluxed for2 hours. Ethyl acetate was added to the reaction mixture. After washingthe organic layer with brine, the organic layer was dried. The solventswere distilled off, and the residue was purified by silica gel columnchromatography to obtain 5.7 g of3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl2-(3-nitrobenzylidene)acetoacetate as a mixture of its E-isomer andZ-isomer (yield: 84%).

(3) To 7.34 g of the benzylidene derivative dissolved in 25 ml ofisopropanol, 2 ml of ethyl 3-aminocrotonate was added. The resultantmixture was refluxed with stirring at 85° C. for 3 hours. After allowingthe reaction mixture to cool down, it was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography, thereby obtaining 7.19 g of 3-ethyl5-[3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate(the compound of Example 6) (yield: 80%).

EXAMPLE 24

After adding 0.11 ml of ethyl acetoacetate and 0.06 ml of conc. aqueousammonia to a solution which contained 382 mg of3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl2-(3-nitrobenzylidene)acetoacetate, which had been obtained in Example23(2), dissolved in 4 ml of isopropanol, the resultant mixture wasstirred at 80° C. for 3.5 hours. After allowing the reaction mixture tocool down, it was concentrated under reduced pressure and the residuewas purified by silica gel column chromatography to obtain 127 mg of thecompound of Example 6 as yellowish powder (yield: 27%).

EXAMPLE 25

To a solution containing 186 mg of3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl acetoacetate, which hadbeen obtained in Example 23(1), in 2 ml of isopropanol, were added 76 mgof 3-nitrobenzaldehyde and 0.07 ml of ethyl 3-aminocrotonate. Theresultant mixture was refluxed with stirring at 85° C. for 4.5 hours.After allowing the reaction mixture to cool down, it was concentratedunder reduced pressure and the residue was purified by silica gel columnchromatography to obtain 261 mg of the compound of Example 6 asyellowish powder (yield: 85%).

EXAMPLE 26

Added to a solution of 309 mg of3-[4-[2-(1-imidazolyl)ethoxy]benzoyloxy]propyl acetoacetate, which hadbeen obtained in Example 23(1), in 3 ml of ethanol were 139 mg of3-nitrobenzaldehyde, 0.12 ml of ethyl acetoacetate and 0.075 ml of conc.aqueous ammonia. The resultant mixture was refluxed with stirring at 80°C. for 5 hours, followed by a further addition of 0.05 ml of conc.aqueous ammonia. The resultant mixture was refluxed with stirring forfurther 1 hour. After allowing the reaction mixture to cool down, it wasconcentrated under reduced pressure and the thus-obtained residue waspurified by silica gel column chromatography to obtain 292 mg of thecompound of Example 6 as yellowish powder (yield: 57%).

We claim:
 1. A 1,4-dihydropyridine-3,5-dicarboxylate compoundrepresented by the following general formula (I): ##STR167## wherein Rmeans an imidazolyl or pyridyl group, R₁ denotes a hydrogen or halogenatom or a nitro or trifluoromethyl group, R₂ is a lower alkyl group, Xis CH or N, A means a lower alkylene group, ##STR168## B being a loweralkylene or O-lower alkylene group, ##STR169## R₄ being a hydrogen atomor lower alkyl group, or ##STR170## m denotes a number of 1-3, and nstands for 1 or
 2. 2. An anti-arteriosclerotic pharmaceuticalcomposition comprising an effective amount of the compound of claim 1 inassociation with a pharmaceutically acceptable carrier.
 3. A method oftreating arteriosclerosis in a subject in need of such treatment whichcomprises administering an effective amount of the compound of claim 1to said subject.